Pathological gambling (PG) has become a major health concern, particularly as gambling opportunities have proliferated. Despite its importance, there are few treatment options with proven efficacy. This application is submitted in response to PAR-99- 134 "Exploratory/Development Grants for MH Intervention/Research" The goal of the project is to conduct a randomized, double-blind comparison of bupropion-SR versus placebo in the treatment of PG. Bupropion will be used because of its reported efficacy in treating attention-deficit hyperactivity disorder (ADHD), and clinical similarities between PG and ADHD. This study will be one of the first of its kind, and has the potential to provide pilot data supporting the efficacy of a novel treatment for PG. We propose to recruit approximately 80 adults with DSM-IV PC during the first two years of the project, and to randomize subjects to bupropion-SR or placebo for a 12-week clinical trial. Subjects will be recruited through physician referral, advertisements in the local media, and by word-of-mouth. Subjects will be screened with the 20-item South Oaks Gambling Screen (SOGS) and the NORC DSM Screen for Gambling Problems (NODS). Those screening positive for PG (SOGS score equal to or >5 and NODS score equal to or >5) will be offered inclusion in the trial provided they meet specified inclusion/exclusion criteria. Baseline assessments will include the Structured Clinical Interview for DSM-IV, the Structured Interview for DSM-IV Personality Disorders, the Yale-Brown Obsessive-Compulsive Scale Modified for PG (YBOCS-PG), the Hollingshead Scale, the NORC Gambling Self-Administered Questionnaire, and the Global Assessment Scale. Baseline assessment will also include a physical examination, an electrocardiogram, urine drug screen, and other screening laboratories. Measures to gauge improvement will include the YBOCS-PG, three Clinical Global Impression scale ratings, a patient self-rated scale, the Hamilton Depression Rating Scale, and the Attention Deficit Hyperactivity Disorder (ADHD) Symptom Checklist. Following a two-week screening period, subjects will be randomized to medication or placebo. The dosage of bupropion-SR will begin at 100 mg twice daily and increased weekly to a total of 400 mg daily. Subjects on placebo will be administered a similar number o tablets. Subjects will be seen at weeks 1, 2, 4, 6, 8, 10, and 12. Adverse events and concomitant medications will be recorded at each visit. We hypothesize that the subjects receiving bupropion will have better symptomatic improvement than subjects receiving placebo. Further, we hypothesize that symptoms consistent with attention-deficit disorder will improve in parallel to the reduction in PG behavior. If bupropion is confirmed as an effective treatment, future studies will include larger samples to help test whether specific subgroups will improve preferentially, and comparisons of bupropion with the SSRI fluvoxamine, and naltrexone, an opiate antagonist, both shown to have efficacy in treating PG.